rs112989722

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000138.5(FBN1):c.6354C>T(p.Ile2118=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FBN1
NM_000138.5 synonymous

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.700

Variant links:

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-48437347-G-A is Pathogenic according to our data. Variant chr15-48437347-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48437347-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.6354C>T	p.Ile2118=	synonymous_variant	52/66	ENST00000316623.10
FBN1	NM_001406716.1 linkuse as main transcript	c.6354C>T	p.Ile2118=	synonymous_variant	51/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FBN1	ENST00000316623.10 linkuse as main transcript	c.6354C>T	p.Ile2118=	synonymous_variant	52/66	1	NM_000138.5	P1
FBN1	ENST00000559133.6 linkuse as main transcript	c.6354C>T	p.Ile2118=	synonymous_variant, NMD_transcript_variant	52/67	1
FBN1	ENST00000674301.2 linkuse as main transcript	c.6354C>T	p.Ile2118=	synonymous_variant, NMD_transcript_variant	52/68
FBN1	ENST00000537463.6 linkuse as main transcript	c.*2117C>T		3_prime_UTR_variant, NMD_transcript_variant	27/31	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250630

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461330

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Marfan syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 22, 2019	The p.Ile2118Ile variant has been identified in 6 individuals with clinical features of Marfan syndrome and segregated in 7 affected relatives (Liu 1997, Miller 2007, Attanasio 2008, Pilop 2009, Pees 2014, Trujillo Quintero 2017). In addition, this variant has been identified as a de novo variant in one affected individual by our laboratory (paternity/maternity not confirmed). This variant has also been identified in 1/19938 East Asian and 1/128572 European chromosomes by gnomAD (gnomAD https://gnomad.broadinstitute.org/). Although this variant does not lead to an amino acid change, functional studies have shown that this variant induces the skipping of exon 51 leading to the in-frame deletion of 22 amino acids (Liu 1997). Therefore, this variant meets criteria to be classified as pathogenic. ACMG/AMP codes applied: PP1_Strong; PM2; PM6; PS3_Moderate; PS4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 24, 2019	- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2014

The c.6354C>T pathogenic mutation (also known as p.I2118I), located in coding exon 51 of the FBN1 gene, results from a C to T substitution at nucleotide position 6354. This nucleotide substitution does not change the amino acid at codon 2118. However, this alteration results in in-frame skipping of the entire exon 51 based on RT-PCR analysis (Liu W et al. Nat Genet. 1997;16(4):328-9). This recurrent alteration disrupts an exonic splicing enhancer and has been reported in multiple patients (Miller TE et al. Genet Med. 2007;9(1):23-33; Attanasio M et al. Clin Genet. 2008;74(1):39-46; Pilop C et al. Circulation. 2009;120(11):983-91; Pees C et al. Clin Genet. 2013). Based on the supporting evidence, c.6354C>T is interpreted as a disease-causing mutation. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 16, 2019

Variant summary: FBN1 c.6354C>T results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publication reports experimental evidence that this variant affects mRNA splicing (Liu_1997, Kashima_2007, Miller_2007). The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. c.6354C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Liu_1997, Miller_2007, Attanasio_2008, Pilop_2009, Trujillo-Quintero_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Published RT-PCR studies demonstrated that c.6354 C>T results in skipping of exon 52 (reported as exon 51) (PMID: 9241263); This variant is associated with the following publications: (PMID: 18435798, 24199744, 34550612, 37107549, 16995940, 11137998, 33801742, 34281902, 36729443, 17224687, 9241263, 28117189, 19720936) -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2022

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 52 (also known as exon 51), but is expected to preserve the integrity of the reading-frame (PMID: 9241263, 16995940, 17224687, 17884807). ClinVar contains an entry for this variant (Variation ID: 16449). This variant has been observed in individual(s) with Marfan syndrome (PMID: 9241263, 17224687, 18435798, 19720936, 24199744, 28117189). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs112989722, gnomAD 0.005%). This sequence change affects codon 2118 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

Cadd

Benign

7.4

Dann

Benign

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over